Physiological role of gonadotropin-releasing hormone (LH-RH) on ovarian function ; phosphoinositide metabolism in granulosa cells.

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In rat granulosa cells, LH-RH induced inositol trisphosphate (IP<D23>D2) formation in a dose-dependent manner. Estrogen production in response to follicular-stimulating hormone (FSH) was reduced by LH-RH in parallel with LH-RH-stimulated IP_3 formation. Half maximal effects of both phenomena occurred at about 10^<-9> M LH-RH. The mirror-image data of stimulation of IP_3 formation and inhibition of estrogen production might suggest tight coupling of stimulated phosphoinositide degradation to suppressed steroidogenesis in the granulosa cells. The aromatase activity, considered as rate-limiting step of estrogen formation in granulosa cells, was measured as the rate of cellular conversion of androstenedione to estrone. FSH exerted a markedly inhibitory effect on the aromatase activity with a lag time of 32h. There were slight effects of FSH on estrone production for the fust 32h, and, thereafter, the rate of estrone production increased progressively. Concurrent incubation with LH-RH decre … More ased the FSH-induced estrone production to the control level. The 50% effective concentration (EC_<50>) for FSH stimulation of estrone production was almost equal in the cells incubated with or without LH-RH, suggesting the noncompetitive inhibitory fashion. The identical data of LH-RH was obtained by protein kinase C activators. Protein kinase C activation might inhibit FSH-induced aromatase induction.It was then undertaken to determine whether persistent receptor occupancy was necessary for LH-RH to exert such actions on granulosa cells, or whether LH-RH actions were continued by a first and transient stimulation by LH-RH, using a competitive antagonist, antide. LH-RH stimulated[ ^<32>Plphosphate incorporation into phosphatidylinositol (PtdIns), which could be terminated by displacement of previously bound LH-RH from its receptor by antide and restarted by reoccupying the receptors with LH-RH. Antide could rapidly prevent LH-RH-stimulated Ptdlns phosphorylation whenever it was added to incubations. An identical effect of antide was observed also in the anti-FSH action of LH-RH. The aromatase activity initiated by FSH was quenched by LH-RH and restarted at a time when LH-RH was removed from its receptor by antide. These two responses associated with the occupancy of LH-RH receptor provide the evidence in favor of a tight coupling of stimulated Ptdlns turnover to suppression of aromatase activation. These data of required continued activation of aromatase activation. Taken together these data of requirement of continued occupancy of receptor for LH-RH to exert its action, LH-RH or LH-RH-like hormone in ovaries, in addition to from pituitary, could participate in the control of steroidogenesis in the ovary in an autocrine or a paracrine manner. Less